Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation

Abstract

How metabolism is reprogrammed during neuronal differentiation is unknown. We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression, together with a switch in pyruvate kinase gene splicing from PKM2 to PKM1, marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation. The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically. Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death, indicating that the shut-off aerobic glycolysis is essential for neuronal survival. The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation to sustain the transcription of metabolic and mitochondrial genes, whose levels are unchanged compared to NPCs, revealing distinct transcriptional regulation of metabolic genes in the proliferation and post-mitotic differentiation states. Mitochondrial mass increases proportionally with neuronal mass growth, indicating an unknown mechanism linking mitochondrial biogenesis to cell size.DOI: http://dx.doi.org/10.7554/eLife.13374.001

MYC Controls Human Pluripotent Stem Cell Fate Decisions through Regulation of Metabolic Flux

“…During cardiomyocyte maturation for example, energy generation switches from a glycolytic to Ox-Phos-dependent mechanism (Lopaschuk and Jaswal, 2010). A similar observation has been made as NPCs transition to neurons in culture (Zheng et al, 2016). During mammalian development the WNT, Sonic hedgehog and Notch signaling pathways link cell fate decisions to metabolic switching in cell types such as brown fat, skeletal muscle and bone (Esen et al, 2013; Teperino et al, 2012).…”

“…This is not the case in DE and Meso that heavily utilize OxPhos for their energy requirements. Cells fated to become neural cells switch their metabolic activity at the midbrain floor plate stage of differentiation, just after they have transitioned through a neural progenitor cell state (Zheng et al, 2016). Interestingly, neural progenitors from the sub-ventricular zone, but not mature neurons, have a high glycolytic rate but undergo switching during neuronal maturation (Candelario et al, 2013).…”

Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration

“…Three of the six intermediate clusters highly expressed ATP and oxidoreduction metabolic genes, and were marked as high-metabolic intermediates (HMI1-3). Because the metabolic process is known to switch from aerobic glycolysis to oxidative phosphorylation throughout neuronal development (Zheng et al, 2016), HMIs are perhaps progenitor cells undergoing the adaptation of the energy metabolism.…”

‘SNO’-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders

“…For instance, under basal conditions, the activity of pyruvate dehydrogenase (PDH) is low in astrocytes, and, therefore, processing of pyruvate, required for entering the tricarboxylic acid (TCA) cycle, is limited [22]. Additionally, during differentiation from neuronal progenitor cells (using predominantly glycolysis) to neurons, expression of hexokinase and lactate dehydrogenase A (LDHA), both of which play critical roles in glycolysis, dramatically declines [23]. …”